ABSTRACT
Recently, we described various stages of CB life cycle to elucidate its molecular pathogenesis in progressive NDDs, including stroke, epilepsy, PD, AD, vascular dementia, HD, MS, ALS, schizophrenia, MDDs, drug addiction, ZIKV disease, FASD, and in nicotinism (Sharma et al. 2013a; Sharma et al. 2013b; Sharma and Ebadi 2014; Sharma et al. 2014; Sharma 2015; Sharma et al. 2015; Sharma et al. 2016; Sharma 2017a; Sharma 2017b). We also reported that CB is generated in the most vulnerable cell in response to severe DPCI due to free radicals-induced oxidative and nitrative stress to the mitochondrial membranes (Sharma 2017a; Sharma et al. 2017b). The mitochondrial membranes are degenerated by free radicals due to lipid peroxidation, which results in the structural and functional breakdown of PUFA. The aggregation and condensation of the degenerated mitochondrial membranes to form CB is an initial attempt to contain highly toxic mitochondrial metabolites such as Cyt-C, which is noncovalently and loosely bond to the inner mitochondrial membranes and can easily disseminate within the cell. The Cyt-C is highly toxic to the mtDNA as well as nuclear DNA, and initiates degenerative apoptosis. In addition, release of other toxic substances, such as AIF-1, 2,3 dihydroxynonenal (a mitochondrial membrane oxidative product), and 8-OH, 2dG (as a DNA oxidative product) can significantly impact microRNA-mediated post-transcriptional activity of genes involved in DNA cell cycle, cell growth, proliferation, differentiation, migration, and development. Hence, the acute step of ICD is energy (ATP)-dependent charnolophagy to maintain intracellular sanitation. A CPS is formed through energy (ATP)-driven CB phagocytosis by the lysosomes. The CPS is transformed to CS, when the phagocytosed CB is hydrolyzed by the lysosomal enzymes. The CS is a single-layered, structurally and functionally labile and can be easily destabilized following subsequent exposure to a free radical attack. The destabilization of CS is 9represented by permeabilization, sequestration, or fragmentation, depending on the intensity and frequency of free radicals generated and the severity of DPCI. The CS releases highly toxic mitochondrial metabolites (acetaldehyde, H2O2, and ammonia) to trigger spontaneous apoptosis due to the formation of CS bodies and their fusion with the plasma membranes. Hence, CS is efficiently exocytosed by energy (ATP)-dependent process to sustain ICD.
